Failure of L-NAME to cause inhibition of nitric oxide synthesis: role of inducible nitric oxide synthase

We addressed the hypothesis that administration of nitric oxide synthase inhibitor, NG -nitro-L-arginine methyl ester (L-NAME) does not result in a sustained suppression of nitric oxide (NO) synthesis, because of a compensatory expression of inducible nitric oxide synthase (iNOS). L-NAME was administered in the drinking water (0.1-1.0 mg/ml) for 7 days to guinea pigs and rats. Nitric oxide synthesis was assessed by [1] ex vivo formation of nitrite in blood vessels and intestine [2] tissue levels of cGMP [3] iNOS gene expression by RT-PCR [4] NADPH diaphorase staining [5] direct assessment of NO release in tissue explants using a microelectrode/electrochemical detection system. Chronic L-NAME administration elevated intestinal cGMP and nitrite levels in guinea pigs (p < 0.05). In rats, intestinal nitrite levels were comparable in control and L-NAME treatment groups, whereas direct assessment of NO release defined a marked increase in the L-NAME group. Chronic L-NAME resulted in an induction of iNOS gene expression in rats and guinea pigs and novel sites of NADPH diaphorase staining in the intestine. We conclude that iNOS expression is responsible for a compensatory increase or normalization of NO synthesis during sustained administration of L-NAME.     

Mediation by nitric oxide of TRH-, but not metoclopramide-stimulated TSH secretion in humans

In order to establish whether nitric oxide (NO) participates in the regulation of thyroid stimulating hormone (TSH) secretion in humans, seven normal men were treated with a placebo (normal saline) or the NO synthase inhibitor L-NAME, given at doses (40 micrograms kg-1 injected plus 50 micrograms kg-1 infused i.v.) previously found to be unable to change blood pressure. Experiments were carried out either in basal conditions or during stimulation of TSH secretion with an i.v. injection of 200 micrograms thyrotropin releasing hormone (TRH) or 10 mg of the dopaminergic antagonist metoclopramide (MCP). Administration of L-NAME did not change the basal secretion of TSH or the TSH response to MCP, but significantly reduced the TSH increase induced by TRH. These data fail to provide evidence of NO involvement in regulation of basal TSH secretion. NO also appears to be without effects on the dopaminergic control of TSH secretion. In contrast, the inhibitory effect of L-NAME on TRH-induced TSH secretion suggests the mediation by NO of the TSH-releasing action of TRH.     

Relative bioavailability of carbinoxamine and phenylephrine from a retard capsule after single and repeated dose administration in healthy subjects

The present study was designed to investigate the role of cardiopulmonary reflex, more specifically the Bezold-Jarisch reflex, in experimental hypertension induced by chronic administration of Nw-nitro-L-arginine methyl ester (L-NAME) (0.5 mg/ml) added to the drinking water for 6 days. The study was performed in male Wistar rats (200-350 g), 9 animals per group. L-NAME ingestion caused a significant increase in resting mean arterial pressure (MAP: 182 +/- 4 mmHg) and heart rate (HR: 447 +/- 20 bpm) when compared to untreated rats (MAP: 112 +/- 3 mmHg and HR: 355 +/- 10 bpm). Cardiopulmonary receptors were chemically stimulated with bolus injections of 5-hydroxytryptamine (5-HT, 4-10 micrograms/kg, iv) followed by measuring the falls in diastolic arterial pressure (DAP) and HR in conscious and freely moving animals. As expected, the responses to intravenous injections of 5-HT consisted of a dose-dependent reduction in HR (from 26 +/- 14 to 175 +/- 25 bpm) and DAP (from 7 +/- 4 to 39 +/- 3 mmHg) in the control rats. Both bradycardia and diastolic hypotension were significantly accentuated in the L-NAME animals (approximately 30%). These data suggest that, in contrast to other models of hypertension, in the present one caused by inhibition of nitric oxide synthesis, the Bezold-Jarisch reflex is exaggerated. This neural dysfunction could be related to changes in the cardiac vagal efferent or effector.     

Inhibition of nitric oxide synthase attenuates osmotic thirst in the rat

Changes in water intake after intraperitoneal injection of a nitric oxide synthase (NOS) inhibitor was studied in the rat. Administration of NW-nitro-L arginine methyl ester (L-NAME) at a dose of 50 mg/kg attenuated osmotic thirst induced by intraperitoneal injection of hypertonic saline, but did not affect spontaneous intake of water and thirst induced by subcutaneous injection of angiotension II. Pretreatment with L-arginine significantly attenuated the inhibition of osmotic thirst evoked with subsequent L-NAME. Administration of NW-nitro-D-arginine methyl ester (D-NAME) altered neither the spontaneous nor the osmotic drinking behavior. These findings suggest that NO may affect the osmotically induced drinking.     

Diinosine polyphosphates, a group of dinucleotides with antagonistic effects on diadenosine polyphosphate receptor

Nitric oxide synthase, an enzyme responsible for nitric oxide (NO) formation has been found in the hypothalamic paraventricular nucleus and median eminence, structures closely associated with regulation of the pituitary activity, and the pituitary gland itself. Nitric oxide modulates the stimulated release of CRH from the rat hypothalamus in vitro, which suggests its role in regulating the secretion of ACTH from the pituitary corticotrops and of corticosterone from the adrenal cortex. The purpose of the present study was to elucidate the yet unknown role of endogenous NO in the HPA response to central cholinergic stimulation in conscious rats. Neither L-arginine an NO precursor, nor the NO synthase blockers N omega-nitro-L-arginine methyl ester (L-NAME) and N omega-nitro-L-arginine (L-NNA) caused any consistent changes in the basal serum corticosterone levels. L-arginine, given in higher doses (120-150 mg/kg ip) 15 min prior to icv carbachol (2 micrograms), markedly diminished the carbachol-induced rise in corticosterone secretion. Systemic pretreatment with the nitric oxide synthase inhibitor L-NAME (5 mg/kg) significantly raised the carbachol-elicited corticosterone response, while addition of L-arginine completely blocked the effect of L-NAME. A similar increase in the carbachol-induced corticosterone response was produced by icv pretreatment with L-NAME (2 micrograms), indicating a central site of the NO interaction with cholinergic stimulation of the HPA response. L-NAME is a weak inhibitor of neuronal NOS itself, and must first be de-estrified to N omega-nitro-L-arginine to potently inhibit this enzyme. Systemic (10 mg/kg) and icv (1 microgram) pretreatment with L-NNA enhanced more effectively the carbachol-induced rise in corticosterone secretion than did pretreatment with L-NAME by either route. These results are the first direct evidence that endogenous NO significantly inhibits the HPA response to central cholinergic, muscarinic receptor stimulation under in vivo conditions.     

The teratogenicity of N(omega)-nitro-L-ariginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in rats

Exposure of gravid rats to the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water or by implanted osmotic minipumps significantly elevates maternal blood pressure, reducing uteroplacental perfusion. Administration by either route causes fetal growth retardation, but oral exposure also causes hind limb reduction malformations. The present study employed both oral and intraperitoneal routes to determine the period of sensitivity to developmental toxicity, dose-response, and possible fetotoxic mechanisms. Hind limb hemorrhage occurred only in litters from dams exposed to oral doses of 1 to 2 mg/mL from gestational days 15 through 17. In contrast to oral exposure, single intraperitoneal injections caused both fore and hind limb reductions at doses of 25 mg/kg and above administered on gestational day 16 and later. Many other exposures that reduce uteroplacental perfusion have been associated with vascular disruptive dysmorphogenesis. These exposures include phenytoin, calcium channel inhibitors, cocaine, and uterine vascular clamping. Limb hemorrhage induced by these exposures is usually limited to distal structures, typically phalanges, and the incidence of affected fetuses rarely exceeds 50%. By contrast, hemorrhage caused by L-NAME frequently involves entire limbs, extending into adjacent flank in severe instances, and 100% of fetuses from treated dams may be affected. The basis of this difference and the differing defect patterns associated with the various routes of exposure are unclear, but the generation of reactive oxygen species during resumption of normal perfusion may play a role in this vascular disruption.     

Inhibition by N omega-nitro-L-arginine methyl ester of the electrocortical arousal response in rats

In rats chronically implanted with cannulae into one lateral cerebral ventricle and recording electrodes onto the fronto-parietal cortex, the effects of systemic or intraventricular administration of the nitric oxide (NO) synthesis inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), on electrocortical (ECoG) arousal response evoked by sound stimulation were studied. In control animals, a single acoustic stimulation (80 dB for 15 s) produced a significant decrease in ECoG total voltage power lasting approximately 25 s. No tolerance developed after repeating the same sound stimulation at 15, 30, 60 min and 24 h intervals. Under these experimental conditions, pretreatment with L-NAME, given systemically (10 mg kg-1, i.p.) or intracerebroventricularly (300 micrograms), significantly reduced the sound-evoked arousal response 1 h and 15 min later, respectively. In conclusion, the present data are in favour of a physiological role of NO in the control of arousal mechanisms.     

ET(B) receptor and nitric oxide synthase blockade induce BQ-123-sensitive pressor effects in the rabbit

Endothelin-1 (0.25 nmol/kg, injected into the left cardiac ventricle) induces a protracted increase of mean arterial pressure that is significantly reduced by the selective ET(A) receptor antagonist BQ-123 (1 and 10 mg/kg) in the anesthetized rabbit. The sole administration of the selective ET(B) antagonist BQ-788 (0.25 mg/kg) induces a pressor response abolished by BQ-123 (1 mg/kg). Concomitant to the increase in mean arterial pressure, BQ-788 induces a significant increase in plasma levels of endothelin-1 and its precursor big endothelin-1. The nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) also increases arterial blood pressure, and the response is reduced dose-dependently by BQ-123 (1 and 10 mg/kg). In addition, the administration of BQ-788 in the presence of L-NAME induced a further increase in arterial blood pressure. The duration of the pressor response to L-NAME is also significantly reduced by an endothelin-converting enzyme inhibitor, phosphoramidon (10 mg/kg). Finally, L-NAME induces an increase in plasma levels of big endothelin-1 but not endothelin-1. Our results illustrate that blockade of either nitric oxide synthase or ET(B) receptors triggers a raise in plasma levels of endothelin-1 or its precursor. These later moieties are suggested to be significantly involved, through the activation of ET(A) receptors, in the pressor effects of L-NAME and BQ-788 in the anesthetized rabbit.     

Chronic inhibition of nitric oxide synthase in Heymann nephritis

Effects of nitric oxide (NO) synthase inhibition on blood pressure and on the course of Heymann nephritis was examined in rats. L-NG-nitroarginine-methylester (L-NAME, 10 mg/100 ml in the drinking water for 12 weeks) was used as an inhibitor of NO synthase. Urinary excretion of guanosine 3',5'-cyclic monophosphate (cGMP), a second messenger of NO, was used as an indirect estimate of NO activity. Rats were divided into the following groups: control, nephritis, L-NAME, and nephritis-L-NAME. Urinary cGMP excretion was lower in the nephritis group (p < 0.05) and in the nephritis-L-NAME group (p < 0.005) compared with controls. Plasma atrial natriuretic peptide (ANP) levels were elevated in the nephritis (p < 0.001) and in the nephritis-L-NAME groups (p < 0.05. L-NAME treatment alone did not have any effect on plasma ANP levels. Blood pressure rose progressively in all L-NAME-treated rats. Most marked albuminuria developed in the nephritis-L-NAME group. No differences in the immunohistological findings were observed between the nephritis and the nephritis-L-NAME groups. NO synthase inhibition causes hypertension and aggravates albuminuria in chronic nephritis. Moreover, nephritis itself may decrease then production of cGMP either as a consequence of blunted NO activity or, in addition, because of ANP resistance. It appears that NO synthase inhibition does not change the immunological course of Heymann nephritis but rather the increased hemodynamic load makes the course of nephritis worse.     

Attenuation by creatine of myocardial metabolic stress in Brattleboro rats caused by chronic inhibition of nitric oxide synthase

1. The present experiment was undertaken to investigate: (a) the effect of nitric oxide synthase (NOS) inhibition, mediated by oral supplementation of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on measures of myocardial energy metabolism and function: (b) the effect of oral creatine supplementation on these variables, in the absence and presence of L-NAME. 2. In one series of experiments, 4 weeks oral administration of L-NAME (0.05 mg ml-1 day-1 in the drinking water) to Brattleboro rats caused significant reductions in myocardial ATP, creatine, and total creatine concentrations and an accumulation of tissue lactate when compared with control animals. Administration of creatine (0.63 mg ml-1 day-1 in the drinking water) for 4 weeks elevated myocardial creatine and total creatine concentrations and reduced lactate accumulation, but did not significantly affect ATP or phosphocreatine (PCr). Concurrent treatment with creatine and L-NAME prevented the reduction in creatine and total creatine concentrations, and significantly attenuated the accumulation of lactate and the reduction in ATP seen with L-NAME alone. 3. In a second series of experiments, 4 weeks treatment with L-NAME and creatine plus L-NAME increased mean arterial blood pressure in conscious Brattleboro rats. Hearts isolated from these animals showed decreased coronary flow and left ventricular developed pressure (LVDP), and total mechanical performance. Treatment with creatine alone had no measurable effect on either mean arterial blood pressure or coronary flow in isolated hearts. However, there was an increase in LVDP, but not in total mechanical performance, because there was a bradycardia. 4. These results indicate that creatine supplementation can attenuate the metabolic stress associated with L-NAME administration and that this effect occurs as a consequence of the action of creatine on myocardial energy metabolism.     

A two-term MEDLINE search strategy for identifying randomized trials in obstetrics and gynecology

In this study, we examined whether endothelin (ET) plays a role in the short-term increase in mean arterial pressure (MAP) after nitric oxide synthase (NOS) inhibition with N(omega)-nitro-L-arginine methyl ester (L-NAME) in stroke-prone spontaneously hypertensive rats (SHRSPs). Experiments were performed by using Inactin-anesthetized male SHRSPs that were pretreated with chlorisondamine to block reflex autonomic cardiovascular effects. Injection of L-NAME (10 mg/kg, i.v.), but not D-NAME, produced rapid and marked increases (74 +/- 3 mm Hg) in MAP that were sustained for >1 h. In SHRSPs that were treated with the ET(A/B) receptor antagonist, L-754,142 (15 mg/kg + 15 mg/kg/h), L-NAME increased MAP by 45 +/- 4 mm Hg (p < 0.0001 compared with L-NAME alone). L-754,142 blocked pressor responses to big ET-1 by >90% but was without effect on pressor responses to norepinephrine. Plasma levels of ET-1 averaged 5 +/- 1 pg/ml in animals given vehicle and were slightly increased in animals given either L-NAME alone (7 +/- 2 pg/ml) or L-754,142 alone (7 +/- 2 pg/ml) but increased markedly when L-NAME and L-754,142 were given together (114 +/- 18 pg/ml). This may relate to an effect of L-754,142 to block ET-receptor-mediated clearance of ET-1. We conclude that ET plays a role in the short-term pressor response after NOS inhibition in SHRSPs.     

Role of nitric oxide in the effect of blood flow on neointima formation

PURPOSE: Neointima formation after arterial injury is inhibited by increased blood flow. The object of this study was to determine whether nitric oxide mediates the effect of increased blood flow on neointima formation. METHOD: Balloon catheter-denuded rat carotid arteries were exposed to increased blood flow or control blood flow by ligation of the contralateral carotid artery. Beginning 2 days before balloon denudation, rats were given either saline vehicle alone or the nitric oxide synthase inhibitor N-nitro-L-arginine-methyl ester (L-NAME) at a dose of 10 mg/kg/day or 2 mg/kg/day intraperitoneally. The normalized neointima area was measured 14 days after denudation. RESULTS: Blood flow was significantly increased by ligation of the contralateral carotid artery for all drug treatments (p<0.008). In rats given saline vehicle only, normalized neointima area was significantly reduced after increased blood flow compared with control blood flow (0.33+/-0.04 compared with 0.48+/-0.03; p=0.006). Systolic blood pressure was significantly elevated by treatment with high-dose L-NAME (p=0.002 compared with vehicle), but was not altered by low-dose L-NAME (p=NS compared with vehicle). Normalized neointima area was not significantly reduced after increased carotid blood flow for rats treated with either dose of L-NAME (p=NS). CONCLUSION: The inhibition of neointima formation by increased blood flow was abolished with hypertensive and nonhypertensive doses of the nitric oxide synthase inhibitor L-NAME, which suggests that the L-NAME effects are independent of systemic hemodynamic alterations. It is concluded that flow-induced inhibition of neointima formation is mediated in part by nitric oxide.     

Tumor necrosis factor-alpha induces emphysema-like pulmonary tissue rebuilding. Changes in type II alveolar epithelial cells

This study has investigated the relative involvement of cholinergic, adrenergic, nitric oxide and tachykininergic transmission in extrinsic neural influences on the lower oesophageal sphincter (LOS) in urethane anaesthetized ferrets. A micromanometric assembly (OD 1.75 mm) incorporating a sleeve sensor was used for high-fidelity oesophageal, LOS and gastric pressure measurement at low perfusion rates (< 0.1 ml/min). The LOS response to vagal and splanchnic nerve stimulation (0.5 ms pulse width, 10 s duration) was frequency- and voltage-dependent. LOS responses to stimulation at 20 V, 10 Hz were investigated in separate groups of animals with either L-NAME (100 mg/kg), hexamethonium (15 mg/kg), guanethidine (5 mg/kg), CP96,345 (NK-1 antagonist, 4 mg/kg), atropine (0.4 mg/kg) or propranolol (1 mg/kg). Propranolol treatment was followed by yohimbine (1 mg/kg) and prazosin (0.25 mg/kg). Vagal stimulation caused an immediate decrease in LOS pressure, followed by increase on cessation of stimulation, followed by a prolonged decrease (77 +/- 2%) for up to 5 min. L-NAME did not affect inhibition, but increased excitation 4-fold (p < 0.001). Guanethidine and CP96,345 had no major effect. Hexamethonium decreased the inhibitory (p < 0.05) and excitatory (p < 0.01) responses. Atropine reduced the excitatory response (p < 0.05). Some inhibition still remained if all treatments were combined. Splanchnic stimulation reduced LOS pressure by 70 +/- 6% for 101 +/- 17 s. L-NAME, guanethidine, hexamethonium and CP96,345 all independently significantly reduced inhibition. The combination of guanethidine and CP96,345 usually abolished splanchnic-induced inhibition. Atropine was without effect. Propranolol (1 mg/kg) changed the splanchnic-induced response from mainly inhibition to excitation (100 +/- 44% increase). LOS responses to noradrenaline (1-10 micrograms close IA) showed similar features to responses to splanchnic stimulation. We conclude that vagal stimulation evokes LOS relaxation via activation of established cholinergic and NANC mechanisms and other, unidentified mechanisms. Splanchnic stimulation activates adrenergic neurones probably via nicotinic and non-nicotinic ganglionic mechanisms, which in turn elicit beta adrenergic inhibitory effects on the LOS. Splanchnic stimulation also antidromically activates spinal afferent fibres. These may release substance P from peripheral myenteric plexus and prevertebral ganglionic endings causing activation of myenteric NANC inhibitory neurones and sympathetic neurones, respectively.     

Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits

To determine if endogenous local levels of nitric oxide (NO) modulate atherogenesis, we studied the effect of inhibiting NO with NG-nitro-L-arginine methyl ester (L-NAME) on early neointima formation in cholesterol-fed rabbits. Male rabbits were fed for 5 weeks with a 0.5% cholesterol diet alone or treated in addition during the last 4 weeks with L-NAME (12 mg/kg per day SC) via osmotic minipump. Endothelial cell function was assessed in isolated aortic rings by vascular reactivity and levels of cyclic GMP. In L-NAME-treated rabbits there was inhibition of endothelium-dependent relaxations to acetylcholine and the calcium ionophore A23187 as well as impaired cyclic GMP accumulation in response to acetylcholine. Neointima formation in the ascending thoracic aorta was assessed by determining media and intima cross-sectional areas with computerized image analysis. Compared with rabbits that consumed the cholesterol diet alone, L-NAME-treated rabbits had significant increases in lesion area (0.29 +/- 0.04 versus 0.15 +/- 0.03 mm2) and in lesion/media ratio (0.06 +/- 0.01 versus 0.03 +/- 0.01). Plasma levels of cholesterol and fluorescent lipid peroxide products were unchanged, suggesting no difference in cholesterol metabolism or oxidation. Because arterial blood pressure was not altered by L-NAME treatment, the increased atherogenesis could not be attributed to an increase in blood pressure. These results indicated that local inhibition of NO accelerates early neointima formation possibly because of modulating monocyte recruitment or foam cell lipid accumulation.     

Cholinergic receptor-mediated responses in the arteriolar and venous vascular beds of the human forearm

Different antihypertensive treatment regimes were studied in rats during long-term inhibition of nitric oxide synthesis. Male Munich Wistar rats (weight 150-200 g) were put on oral L-nitro-arginine methyl ester (L-NAME, 50 mg/l drinking water) for 12 weeks. The control group (n = 16) received only tap water. Six weeks after starting L-NAME administration rats were divided into 7 groups (n = 13 in each group: group 1, no treatment; group 2, l-arginine 1 g/l drinking water; group 3, doxazosin 30 mg/kg/day; group 4, felodipine 25-30 mg/kg/day; group 5, losartan 40 mg/kg/day; group 6, metoprolol 300-350 mg/kg/day, and group 7, ramipril 1 mg/kg/day. Systolic blood pressure (sBP) was measured in the conscious rat 1, 6, and 12 weeks after study begin. After a treatment period of 6 weeks albuminuria, glomerular filtration rate (GFR) and renal plasma flow (RPF; inulin and p-aminohippuric acid clearance) were analyzed. All rats showed a significant increase in sBP under 6 weeks of L-NAME administration. Control rats remained normotensive during the whole study period. Rats receiving L-NAME without antihypertensive treatment showed a further increase in sBP after 12 weeks. Blood pressure was lowered in all treated animals, except in rats receiving l-arginine. Values for GFR were lowest in the placebo group, the l-arginine group and in rats receiving felodipine (p < 0.05 compared to the control group). RPF was lowest in the placebo group, the l-arginine group, the felodipine group and the ramipril group (p < 0.05 compared to the control group).(ABSTRACT TRUNCATED AT 250 WORDS)     

Quality of life assessment in reflux disease

It has been suggested that inhibitors of nitric oxide synthesis are of value in the treatment of hypotension during sepsis. In this pilot study, we examined the effects of inhibition of nitric oxide synthesis by continuous infusion of N(omega)-nitro-L-arginine methyl ester (L-NAME) at 1.5 mg/kg/h in a patient with severe septic shock. L-NAME produced a rise in mean arterial blood pressure and systemic vascular resistance; catecholamine infusion could be reduced. Parallel to these findings, there was a 50% reduction in cardiac output and a 5-fold rise in pulmonary vascular resistance, which resulted in severe pulmonary hypertension after 3 h of L-NAME infusion, for which the infusion had to be stopped. Following the termination of L-NAME infusion, pulmonary artery pressure and blood pressure returned to baseline values, although pulmonary and systemic vascular resistance remained elevated for several hours. We conclude that nitric oxide appears to play a role in the cardiovascular derangements during human sepsis. Inhibition of nitric oxide synthesis with L-NAME can increase blood pressure and systemic vascular resistance. However, reduced cardiac output and pulmonary hypertension are possible side effects of continuous NO synthase inhibition. These side effects necessitate careful monitoring and may hinder the clinical application of NO synthase inhibitors.     

Hemorrhagic bullous lesions in Henoch-Sch?nlein purpura

A microinjection of endothelin-1 (ET-1; 10 pmol) into the superior colliculus (SC) of anaesthetised rats caused a decrease in blood pressure. Microinjection into the same nucleus of Nomega-nitro-L-arginine methyl ester (L-NAME; 0.1, 0.5, 1 micromol), an L-arginine analogue and a potent inhibitor of nitric oxide (NO) synthase, increased the basal mean arterial blood pressure. Treatment of SC with L-NAME (1 micromol) did not affect the depressor response induced by injection of ET-1 (10 pmol), into the SC, at the peak of the pressor response to L-NAME. In addition, L-arginine L-ARG) (1 micromol), the substrate for NO synthase, microinjected into the superior colliculus prior to ET-1 did not significantly increase the depressor response to ET-1. These findings, therefore, suggest that within the SC the nitric oxide synthesis does not affect depressor responses induced by ET-1.(c) 1998 The Italian Pharmacological Society     

Arachidonic acid and its metabolites are involved in the expression of morphine dependence in guinea-pig isolated ileum

This study was undertaken to determine if the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), is a competitive antagonist of muscarinic receptors in vivo. Cats were anesthetized with pentobarbital (36 mg/kg, i.p.). Five peripheral muscarinic responses were characterized based on their sensitivity to intravenous administration of atropine (1-100 microg/kg), pirenzepine (1-100 microg/kg) or gallamine (30-3000 microg/kg) as follows: (1) muscarinic ganglionic transmission through the superior cervical ganglion to the nictitating membrane (M1), (2) electrically elicited vagal bradycardia (M2), (3) neurally evoked sudomotor responses (M3; non-endothelial), (4) basal pupil tone in sympathectomized cats (M3; non-endothelial) and (5) methacholine-induced depression of arterial blood pressure (M3; endothelial). Additional groups of animals were administered L-NAME (50 mg/kg, i.v.) to determine if this agent would alter activation of these muscarinic systems. L-NAME was devoid of effect on responses elicited by stimulation of muscarinic M1, M2 and M3 (non-endothelial) receptors. In contrast, L-NAME significantly reduced the depressor responses to i.v. methacholine (M3; endothelial), as did its non-alkyl ester congener, L-NA (NG-nitro-L-arginine; 25 mg/kg, i.v.). These results support the conclusion that although L-NAME inhibits synthesis of nitric oxide in vascular endothelial cells, it is not a generalized muscarinic receptor antagonist in vivo.     

Chronic hypertension leads to hyperinsulinemia in Sprague-Dawley rats treated with nitric oxide synthase inhibitor

Insulin resistance and hypertension, as well as dyslipidemia, frequently cooccur. Evidence that nitric oxide (NO) plays a crucial role in the long-term regulation of systolic blood pressure led us to examine whether enhanced vasoconstriction and hypertension induced by NO synthase inhibitor could lead to insulin and lipid disorders. NG-Nitro-L-arginine methyl-ester (L-NAME), an inhibitor of NO synthase, was given for 4 weeks in drinking water (100 mg/kg/day) to 12 Sprague-Dawley rats. Another nine rats received both L-NAME and verapamil (100 mg/kg/day), whereas 12 animals fed rat chow only served as controls. Systolic blood pressure was measured weekly by the indirect tail cuff method. Blood samples were taken at the beginning of the experiment, and after 2 and 4 weeks from all rats. The samples were assayed for insulin, glucose, and triglyceride concentrations. L-NAME treatment resulted in a marked and sustained increase in systolic blood pressure from 130+/-7 to 171+/-3 mm Hg by the second week, which was succeeded by a significant elevation in insulin level at the end of 4 weeks, from 2.3+/-1.8 to 5.4+/-2.0 ng/mL. Triglycerides and glucose were unaffected throughout the experiment. The combination of L-NAME and the NO-independent vasodilator, verapamil, attenuated the hypertension induced by L-NAME and prevented the following rise in insulin level. Data suggest that chronic elimination of NO after chronic inhibition of NO synthase may lead to a state of hyperinsulinemia, possibly as an outcome of insulin resistance.     

A prospective study of omeprazole suspension to prevent clinically significant gastrointestinal bleeding from stress ulcers in mechanically ventilated trauma patients

We recently reported that administration of Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) production, activates the vascular and cardiac renin-angiotensin systems and causes vascular thickening and myocardial hypertrophy in rats with perivascular and myocardial fibrosis. It has been reported that aldosterone may contribute to the development of cardiac fibrosis, but it is not known whether inhibition of NO synthesis affects angiotensin II (Ang II) receptor gene expression and aldosterone secretion. The aim of this study was to investigate the effect of NO inhibition on the expression of Ang II receptors in the adrenal gland and on aldosterone secretion in rats. Wistar King A rats received normal water, L-NAME alone (1 mg/mL in the drinking water), or L-NAME and the alpha1-adrenergic receptor blocker bunazosin (0.1 mg/mL in the drinking water) for 1 week. After 1 week of treatment with L-NAME, systolic blood pressure, plasma aldosterone concentration (PAC), and mRNA level and number of Ang II type 1 receptor (AT1-R) were increased. Plasma renin activity, serum angiotensin-converting enzyme activity, and the number of AT2-R were unchanged. Although addition of bunazosin to L-NAME restored systolic blood pressure to the control level, PAC and AT1-R numbers remained significantly higher than those of control level. These results suggest that the increased AT1-R number and PAC induced by the inhibition of NO synthesis were independent of blood pressure and systemic renin-angiotensin system. Therefore, hypertension and myocardial fibrosis induced by NO blockade may be due in part to an elevation of PAC caused by increased AT1-R in the adrenal gland.